Brain metastasis is one of the most difficult challenges facing oncology. Metastatic tumors are resistant to most chemotherapy agents. The treatments for brain metastasis are primarily whole brain and focused radiotherapy, with surgical resection of tumors in a minority of cases. Most chemotherapy regimens involve 2-3 agents such as cisplatin, cyclophosphamide, etoposide, teniposide, mitomycin, irinotecan, vinorelbine, etoposide, ifosfamide, temozolomide and fluorouracil (5-FU). These are administered in combination with radiotherapy. The effect of these chemotherapies on prolonging survival is generally less than a year. A fairly new chemotherapy for brain tumors is temozolomide used with whole-brain irradiation. Results are preliminary but temozolomide appears to have some limited effect on the response rate compared to radiation alone and appears to have some clinical activity in combination with radiation in phase II trials.
Despite intense efforts, the limited medical options available for brain metastasis have remained poor and too often more palliative than therapeutically effective. This state of affairs has been long recognized but, to date, significant advances have not materialized. Consequently, there is a great and present medical need for new therapeutic approaches and pharmaceuticals effective at treating brain metastasis.
The disclosure below discusses endothelin receptor antagonists in relation to brain metastasis. Endothelin-1 (hereafter “ET-1”), a vasoactive peptide, is produced primarily in endothelial, vascular smooth muscle, and epithelial cells. ET-1 exerts its physiological effect via two high-affinity G-protein-coupled receptors, the endothelin-A (hereafter “ETA”) and the endothelin-B (hereafter “ETB”) receptors. Endothelin receptor antagonists (ERAs) are a well established class of compounds capable of inhibiting these endothelin receptors (hereafter “ETRs”). Within this class are subclasses of antagonists specific to ETA or ETB and a subclass effective against both (dual specificity). One member of the dual specificity subclass, bosentan, is currently approved for use in treating pulmonary arterial hypertension.
Certain ERAs have been investigated for use in cancer therapy. [Nelson J B, et al., Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer, 2008 Nov. 1; 113(9):2376-8.; Chiappori A A, et al. Phase I/II study of atrasentan, an ETA receptor antagonist, in combination with paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer. Clin Cancer Res, 2008 Mar. 1; 14(5):1464-91 These studies have largely excluded patients with active brain metastasis. Ibid. This exclusion is done on the general view that existing brain metastases will not respond to treatment and, thus, morbidity and symptoms due to these metastases would mask the effects of the test treatment on the primary tumor, [Carden C P, et al., Eligibility of patients with brain metastases for phase I trials: time for a rethink? The Lancet Oncology, Vol 9, Issue 10, Pages 1012-1017, October 2008 doi:10.1016/S1470-2045(08)70257-2.] This standard clinical trial design strategy serves to emphasize the general expectation that therapies effective against primary tumors and even non-brain metastasis tumors will fail to effect brain metastasis tumors.